The present invention relates to substituted benzylthiazolidine-2,4-dione derivatives effective for the prevention and/or therapy of metabolic diseases such as diabetes and hyperlipidemia as agonists of peroxisome proliferator-activated receptor (abbreviated as PPAR) being nuclear receptor, in particular, as agonists of human PPAR, their addition salts, processes for preparing them, and medicinal compositions containing these compounds.
The peroxisome proliferator-activated receptor(PPAR) is a ligand-dependent transcription factor that belongs to nuclear receptor superfamily similarly to steroid receptor, retinoid receptor, thyroid receptor, etc., and three isoforms (xcex1 type, xcex2(or xcex4) type and xcex3 type) with different histological distribution have been identified hitherto in human and various animal species (Proc. Natl. Acad. Sci., 1992, 89, 4653). Thereamong, the PPARxcex1 is distributed in the liver, kidney, etc. with high catabolic capacity for fatty acids and, particularly high expression is recognized in the liver, (Endo-crinology, 1995, 137, 354), positively or negatively controlling the expressions of genes related to the metabolism and the intracellular transport of fatty acids (e.g. acyl CoA synthetic enzyme, fatty acid-binding protein and lipoprotein lipase) and apolipoprotein (AI, AII, CIII) genes related to the metabolisms of cholesterol and neutral lipid. The PPARxcex2 is expressed ubiquitously in the tissues or organisms, including nerve cells. At present, the physiological significance of PPARxcex2 is unclear. The PPARxcex3 is highly expressed in the adipocytes and contributed to the differentiation of adipocytes (J. Lipid Res., 1996, 37, 907). In this way, each isoform of PPAR play specific functions in the particular organs and tissues.
Moreover, it is reported that a knock-out mouse of PPARxcex1 exhibits hypertriglyceridemia with ageing and becomes obesity mainly by increasing the white adipose tissues (J. Biol. Chem., 1998, 273, 29577), hence the relevance between activation of PPARxcex1 and decreasing action of lipids (cholesterol and triglyceride) in blood is suggested strongly.
On the other hand, fibrates and statins are widely used so far as the therapeutic drugs for hyperlipidemia. However, the fibrates have only weak decreasing action of cholesterol. while the statins have weak decreasing action of free fatty acids and triglycerides. Moreover, with respect to the fibrates, various adverse effects such as gastrointestinal injury, anthema, headache, hepatic disorder, renal disorder and biliary calculus are reported. The reason is considered to be due to that the fibrates exhibit extensive pharmacological function.
On the other hand, it is ascertained that the major intracellular target proteins of Troglitazone, Pioglitazone and Rosiglitazone, a series of thiazolidine-2,4-dione derivatives that are therapeutic drugs for type II diabetes (noninsulin-dependent diabetes) and exhibit blood sugar-decreasing action, improving action on hyperinsulinemia, etc. is PPARxcex3, and these drugs increase the transactivation of PPARxcex3 (Endocrinology, 1996, 137, 4189, Cell., 1995, 83, 803, Cell., 1995, 83, 813). Hence, PPARxcex3-activator (agonist) that can augment the transactivation of PPARxcex3 is important as antidiabetic drug.
As described, when considering the role of transcription factor called PPAR on the function on adipocytes and the controlling mechanisms of glucose metabolism and lipid metabolism, if a compound that binds directly to as a ligand of PPAR, in particular, human PPAR and can activate human PPAR could be created, it would be reasonable to expect the medicinal use as a compound that exhibits blood glucose-decreasing action and/or decreasing action of lipids (both of cholesterol and neutral lipid) in blood due to very specific mechanism.
For compounds having an affinity to PPARxcex1 as ligands of PPARxcex1, HETE (hydroxyeicosatetraenoic acid) produced via oxidation with cytochrome P-450 and eicosanoides in HEPE (hydroxyeicosapentaenoic acid) groups, in particular, 8-HETE, 8-HEPE, etc. are reported in addition to LTB., being a metabolite of arachidonic acid (Proc. Natl. Acad. Sci., 1997, 94, 312). However, these endogenous unsaturated fatty acid derivatives are unstable metabolically and chemically and cannot be offered as medicinal drugs.
Moreover, with Toroglitazone, the occurrence of serious adverse effect on liver is reported rarely, hence the development of a therapeutic drug for type II diabetes with effectiveness and high safety is being sought.
Now, as compounds with similar structure to the inventive substituted benzylthiazolidine-2,4-dione derivatives, thiazolidine-2,4-dione derivatives in Japanese Unexamined Patent Publication Nos. Sho 55-22636, Sho 60-51189, Sho 61-85372, Sho 61-286376, Hei 1-131169, Hei 2-83384, Hei 5-213913, Hei 8-333355, Hei 9-48771 and Hei 9-169746, European Patent Open No. 0441605, WO-92/07839, etc. are known. However, all of these compounds are thiazolidine-2,4-dione derivatives with different structure from the inventive compounds.
With regard to patents etc. reporting the agonistic effect on PPARxcex1, WO-97/25042, WO-97/36579, etc. are reported, but all of these have different structure from the inventive compounds and the transactivation function of PPARxcex1 is also never satisfied in strength.
Both the hyperlipidemia and the diabetes are risk factors of arterosclerosis and, from a viewpoint of the prevention of arterosclerosis, in particular, coronary arterosclerosis, the development of a therapeutic drug for metabolic diseases with effectiveness and high safety is desired clinically.
As a result of diligent studies paying an attention to such specific role on the lipid metabolism of human PPAR, aiming at the creation of structurally novel drug with effectiveness and high safety as a therapeutic drug for diabetes and a therapeutic drug for hyperlipidemia, the inventors have found that novel substituted benzylthiazolidine-2,4-dione derivatives represented by a following general formula (1) have excellent transactivation function on human PPAR, and exhibit the blood glucose-decreasing action and the lipid-decreasing action, leading to the completion of the invention.
Namely, the invention relates to substituted benzylthiazolidine-2,4-dione derivatives represented by a general formula (1) 
[wherein the bond mode of A denotes xe2x80x94CH2CONHxe2x80x94, xe2x80x94NHCONHxe2x80x94, xe2x80x94CH2CH2COxe2x80x94 or xe2x80x94NHCOCH2xe2x80x94, and B denotes a lower alkyl group with carbon atoms of 1 to 4, lower alkoxy group with carbon atoms of 1 to 3, halogen atom, trifluoromethyl group, trifluoro-methoxy group, phenyl group which is unsubstituted or may have substituents, phenoxy group which is unsubstituted or may have substituents or benzyloxy group which is unsubstituted or may have substituents], their medicinally acceptable salts and their hydrates.
The salts of the compounds represented by the general formula (1) in the invention are of common use and metal salts, for example, alkali metal salts (e.g. sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g. calcium salt, magnesium salt, etc.), aluminum salt, and other pharmacologically acceptable salts are mentioned.
Moreover, the compounds represented by the general formula (1) in the invention sometimes include optical isomers based on thiazolidine-2,4-dione ring portion, but all of such isomers and their mixtures are to be included in the scope of the invention.
Furthermore, for the compounds represented by the general formula (1), the existence of various tautomers is considered. These are, for example, as shown in the following formulae. 
[wherein the bond mode of A denotes xe2x80x94CH2CONHxe2x80x94, xe2x80x94NHCONHxe2x80x94, xe2x80x94CH2CH2COxe2x80x94 or xe2x80x94NHCOCHxe2x80x94, and B denotes a lower alkyl group with carbon atoms of 1 to 4, lower alkoxy group with carbon atoms of 1 to 3, halogen atom, trifluoromethyl group, trifluoromethoxy group, phenyl group which is unsubstituted or may have substituents, phenoxy group which is unsubstituted or may have substituents or benzyloxy group which is unsubstituted or may have substituents].
In the general formula (l) aforementioned, all of these isomers and their mixtures are to be included in the scope of this invention.
In the general formula (1) of the invention, for xe2x80x9clower alkyl group with carbon atoms of 1 to 4xe2x80x9d, straight chain or branched ones with carbon atoms of 1 to 4 such as methyl, ethyl, propyl, isopropyl and butyl are mentioned. For xe2x80x9clower malkoxy group with carbon atoms of 1 to 3xe2x80x9d, straight chain or branched ones with carbon atoms of 1 to 3 such as methoxy, ethoxy, isopropoxy and propoxy are mentioned.
For xe2x80x9chalogen atomsxe2x80x9d, fluorine atom, chlorine atom, bromine atom and iodine atom are mentioned. For substituents acceptable in xe2x80x9cphenyl group which is unsubstituted or may have substituents, phenoxy group which is unsubstituted or may have substituents or benzyloxy group which is unsubstituted or may have substituentsxe2x80x9d, lower alkyl group with carbon atoms of 1 to 4, lower alkoxy group with carbon atoms of 1 to 3, and halogen atom are mentioned.
According to the invention, the compounds (1a), the bond mode of A portion being xe2x80x94NHCOCH2xe2x80x94 in the said general formula (1), can be prepared, for example, through following processes (Scheme 1). 
Namely, the compounds (1a), the bond mode of A portion being xe2x80x94NHCOCH2xe2x80x94 in the general formula (1), can be prepared as follows. (first process) 4-Methoxybenzaldehyde (2) was treated with ethyl 2-chloro-2-(methylthio)acetate in the presence of Lewis acid (Chem. Pharm. Bull., 1982, 30, 915) to obtain ethyl 2-methylthio-2-(5-formyl-2-methoxyphenyl)acetate (3). Then, reacting (second process) (3) with thiazolidine-2,4-dione in the presence of catalyst, and subsequent elimination (third process) of methylthio group of ethyl 2-methylthio-2-[5-[(2,4-dioxothiazolidin-5-ylidene)methyl]-2-methoxyphenyl]acetate (4), and hydrolysis (fourth process) of the ethyl ester portion of ethyl 2-[5-[(2,4-dioxothiazolidin-5-ylidene)methyl]-2-methoxyphenyl]acetate (5), to give 2-[5-[(2,4-dioxothiazolidin-5-ylidene)methyl]-2-methoxyphenyl]acetic acid (6). Then reacting (fifth process) (6) with compounds represented by the general formula (8) 
[wherein B denotes a lower alkyl group with carbon atoms of 1 to 4, lower alkoxy group with carbon atoms of 1 to 3, halogen atom, trifluoromethyl group, trifluoromethoxy group, phenyl group which is unsubstituted or may have substituents, phenoxy group which is unsubstituted or may have substituents or benzyloxy group which is unsubstituted or may have substituents], and subsequent reduction (sixth process) of the double bond of the general formula (7) obtained 
[wherein B denotes a lower alkyl group with carbon atoms of 1 to 4, lower alkoxy group with carbon atoms of 1 to 3, halogen atom, trifluoromethyl group, trifluoromethoxy group, phenyl group which is unsubstituted or may have substituents, phenoxy group which is unsubstituted or may have substituents or benzyloxy group which Is unsubstituted or may have substituents].
The first process can be performed in a solvent such as methylene chloride, chloroform or nitrobenzene. As the Lewis acid, aluminum chloride, tin chloride, boron trifluoride or the like can be used. The reaction can be performed at the reaction temperature of xe2x88x9220xc2x0 C. to 150xc2x0 C., preferably at refluxing temperature of the solvent.
The second process can be performed in a solvent such as benzene, toluene, xylene, ethanol or acetic acid, or without solvent. As the catalyst, secondary amine such as piperidine or pyrrolidine, or ammonium acetate can be used. The reaction can be performed at the reaction temperature of 0xc2x0 C. to 150xc2x0 C., preferably at refluxing temperature of the solvent.
The reaction of the third process can be performed in a solvent such as acetic acid or hydrochloric acid, by reacting metallic zinc, zinc amalgam or zinc-copper alloy. The reaction can be performed at a reaction temperature of xe2x88x9210xc2x0 C. to 100xc2x0 C., preferably at 0xc2x0 C. to room temperature.
The fourth process can be performed under acidic condition. For the acidic condition, hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid or their mixtures, the mixed solvents of these acids with organic solvent such as sulfolane, or the like are used. The reaction can be performed at a reaction temperature of 0xc2x0 C. to 150xc2x0 C., preferably at refluxing temperature of the solvent.
The fifth process can be performed by leaving the carboxyl group as it is, or converting it to the reactive derivative.
In the case of the reaction using the reactive derivative, the reaction can be performed in a solvent such as methylene chloride, chloroform, dioxane or N,N-dimethylformamide in the presence or absence of, for example, alkali metal hydride such as sodium hydride, alkali metal hydroxide such as sodium hydroxide, alkali metal carbonate such as potassium carbonate, or organic base such as pyridine or triethylamine as a base.
In the case of conducting the reaction by leaving the carboxylic acid as it is, the reaction can be performed in a solvent such as methylene chloride, chloroform, dioxane or N,N-dimethylformamide in the presence of condensing agent in lthe presence or absence of base, and further in the presence or absence of additive.
As the condensing agent, for example, dicyclohexylcarbodiimide, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, diethyl cyanophosphate, diphenylphosphoric azide, carbonyldiimidazole or the like can be mentioned. As the base, for example, alkali metal hydroxide such as sodium hydroxide, alkali metal carbonate such as potassium carbonate, or organic base such as pyridine or triethylamine can be mentioned. As the additive, N-hydroxybenzotriazole, N-hydroxysuccinimide, 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine or the like can be mentioned. The reaction can be performed at the reaction temperature of xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably at 0xc2x0 C. to 50xc2x0 C.
The sixth process can be performed at a hydrogen pressure of 98.1 kPa to 491 kPa in a solvent such as ethanol, methanol, tetrahydrofuran, ethyl acetate or N,N-dimethylformamide in the presence of metallic catalyst such as palladium on activated carbon, platinum on activated carbon, platinum oxide or rhodium on alumina. The reaction can be performed at a reaction temperature of 0xc2x0 C. to 100xc2x0 C., preferably at room temperature to 80xc2x0 C.
Moreover, compounds, the bond mode of A portion being xe2x80x94NHCOCH2xe2x80x94 in the said general formula (1), can also be prepared, for example, through following processes (Scheme 2). 
Namely, compounds (1a). the bond mode of A portion being xe2x80x94NHCOCH2xe2x80x94 in the general formula (1), can be prepared by reducing (seventh process) ethyl [5-[(2,4-dioxothiazolidin-5-ylidene)methyl]-2-methoxyphenyl]acetate (5) to obtain ethyl [5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxyphenyl]acetate (9). Then hydrolyzing (eighth process) (9) to obtain 2-[5-[(2,4-dioxothiazolidin-5-ylidene)methyl]-2-methoxyphenyl]acetic acid (10), and by reacting (ninth process) (10) with compounds represented by the general formula (8) 
[wherein B denotes a lower alkyl group with carbon atoms of 1 to 4, lower alkoxy group with carbon atoms of 1 to 3, halogen atom, trifluoromethyl group, trifluoromethoxy group, phenyl group which is unsubstituted or may have substituents, phenoxy group which is unsubstituted or may have substituents or benzyloxy group which is unsubstituted or may have substituents].
The seventh process can be performed at a hydrogen pressure of 98.1 kPa to 491 kPa in a solvent such as ethanol, methanol, tetrahydrofuran, ethyl acetate or N,N-dimethylformamide in the presence of metallic catalyst such as palladium on carbon, platinum on carbon, platinum oxide or rhodium on alumina. The reaction can be performed at a reaction temperature of 0xc2x0 C. to 100xc2x0 C., preferably at room temperature to 80xc2x0 C.
The hydrolysis of the eighth process can be performed under acidic condition. For the acidic condition, hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid or their mixtures, the mixed solvents of these acids with organic solvent such as sulfolane, or the like are used. The reaction can be performed at a reaction temperature of 0xc2x0 C. to 150xc2x0 C., preferably at refluxing temperature of the solvent.
The reaction of the ninth process can be performed by leaving the carboxyl group as it is, or converting it to the reactive derivative.
In the case of the reaction using the reactive derivative, the reaction can be performed in a solvent such as methylene chloride, chloroform, dioxane or N,N-dimethylformamide in the presence or absence of, for example, alkali metal hydride such as sodium hydride, alkali metal hydroxide such as sodium hydroxide, alkali metal carbonate such as potassium carbonate, or organic base such as pyridine or triethylamine as a base.
In the case of conducting the reaction by leaving the carboxylic acid as it is, the reaction can be performed in a solvent such as methylene chloride, chloroform, dioxane or N,N-dimethylformamide in the presence of condensing agent in the presence or absence of base, and in the presence or absence of additive.
As the condensing agent, for example, dicyclohexylcarbodiimide, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, diethyl cyanophosphate, diphenylphosphoric azide, carbonylduimidazole or the like can be mentioned. As the base, for example, alkali metal hydroxide such as sodium hydroxide, alkali metal carbonate such as potassium carbonate, or organic base such as pyridine or triethylamine can be mentioned. As the additive, N-hydroxybenzotriazole, N-hydroxysuccinimide, 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine or the like can be mentioned. The reaction can be performed at the reaction temperature of xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably at 0xc2x0 C. to 50xc2x0 C.
Moreover, compounds, the bond mode of A portion being xe2x80x94NHCONHxe2x80x94 (1b) or xe2x80x94CH2CONHxe2x80x94 (1c) in the general formula (1), can be prepared, for example, through the following processes (Scheme 3). 
Namely, compounds, the bond mode of A portion being xe2x80x94NHCONHxe2x80x94 (1b) or xe2x80x94CH2CONHxe2x80x94 (1c) in the general formula (1), can be prepared by nitrating (tenth process) 5-[(4-methoxyphenyl)methyl]thiazolidine-2,4-dione (11), then reducing (eleventh process) 5-[(4-methoxy-3-nitro-phenyl)methyl]thiazolidine-2,4-dione (12) to give 5-[(3-amino-4-methoxyphenyl)methyl]thiazolidine-2,4-dione (13). Then by condensing (twelfth process, thirteenth process) (13) with compounds represented by the general formula (26) 
[wherein B denotes a lower alkyl group with carbon atoms of 1 to 4, lower alkoxy group with carbon atoms of 1 to 3, halogen atom, trifluoromethyl group, trifluoromethoxy group, phenyl group which is unsubstituted or may have substituents, phenoxy group which is unsubstituted or may have substituents or benzyloxy group which is unsubstituted or may have substituents], or with compounds represented by the general formula (27) 
[wherein B denotes a lower alkyl group with carbon atoms of 1 to 4, lower alkoxy group with carbon atoms of 1 to 3, halogen atom, trifluoromethyl group, trifluoromethoxy group, phenyl group which is unsubstituted or may have substituents, phenoxy group which is unsubstituted or may have substituents or benzyloxy group which is unsubstituted or may have substituents].
The tenth process can be performed by reacting nitrating agent such as concentrated nitric acid, fuming nitric or the mixture of concentrated nitric acid with concentrated sulfuric acid (mixed acid) in a solvent such as methylene chloride or chloroform, or without solvent. The reaction can be performed at the reaction temperature of xe2x88x9220xc2x0 C. to 120xc2x0 C., preferably at 0xc2x0 C. to 100xc2x0 C.
The eleventh process can be performed by reduction at a hydrogen pressure of 98.1 kPa to 491 kPa in a solvent such as ethanol, ethyl acetate, tetrahydrofuran or N,N-dimethylformamide using a catalyst such as palladium on carbon, rhodium on alumina orplatinum oxide. The reaction can be performed at the reaction temperature of 0xc2x0 C. to 100xc2x0 C., preferably at room temperature to 80xc2x0 C.
The twelfth process can be performed in a solvent such as ethyl acetate, tetrahydrofuran or N,N-dimethylformamide. The. reaction can be performed at the reaction temperature of xe2x88x9220xc2x0 C. to 150xc2x0 C., preferably at 0xc2x0 C. to 100xc2x0 C.
The thirteenth process can be performed by leaving carboxyl group as it is, or converting it to reactive derivative.
As the xe2x80x9creactive derivative of carboxyl groupxe2x80x9d, acid chloride, acid bromide, acid anhydride, carbonylimidazole or the like can be mentioned. In the case of the reaction using reactive derivative, the reaction can be performed in a solvent such as dioxane or N,N-dimethylformamide in the presence or absence of, for example, alkali metal hydride such as sodium hydride, alkali metal hydroxide such as sodium hydroxide, alkali metal carbonate such as potassium carbonate, or organic base such as pyridine or triethylamine as a base.
In the case of conducting the reaction by leaving the carboxylic acid as it is, the reaction can be performed in a solvent such as methylene chloride, chloroform, dioxane or N,N-dimethylformamide in the presence of condensing agent in the presence or absence of base, and in the presence or absence of additive.
As the condensing agent, for example, dicyclohexylcarbodiimide, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, diethyl cyanophosphate, diphenylphosphoric azide, carbonyldiimidazole or the like can be mentioned. As the base, for example, alkali metal hydroxide such as sodium hydroxide, alkali metal carbonate such as potassium carbonate, or organic base such as pyridine or triethylamine can be mentioned. As the additive, N-hydroxybenzotriazole, N-hydroxysuccinimide, 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine or the like can be mentioned. The reaction can be performed at the reaction temperature of xe2x88x9220xc2x0 C. to 100xc2x0 C. preferably at 0xc2x0 C. to 50xc2x0 C.
Moreover, compounds, the bond mode of A portion being xe2x80x94NHCONHxe2x80x94 (1b) or xe2x80x94CH2CONHxe2x80x94 (1c) in the general formula (1), can also be prepared through following processes (Scheme 4). 
Namely, compounds, the bond mode of A portion being xe2x80x94NHCONHxe2x80x94 (1b) or xe2x80x94CH2CONHxe2x80x94 (1c) in the general formula (1), can be prepared by reacting (fourteenth process) 4-methoxy-3-nitrobenzaldehyde (14) with thiazolidine-2,4-dione, then reducing (fifteenth process) the nitro group of 5-[(4-methoxy-3-nitrophenyl)methylidene]thiazolidine-2,4-dione (15) to give 5-[(3-amino-4-methoxyphenyl)methylidene]thiazolidine-2,4-dione (16), and condensing (sixteenth process, seventeenth process) (16) with the compounds represented by the general formula (27) 
[wherein B denotes a lower alkyl group with carbon atoms of 1 to 4, lower alkoxy group with carbon atoms of 1 to 3, halogen atom, trifluoromethyl group, trifluoromethoxy group, phenyl group which is unsubstituted or may have substituents, phenoxy group which is unsubstituted or may have substituents or benzyloxy group which is unsubstituted or may have substituents], or with the compounds represented by the general formula (26) 
[wherein B denotes a lower alkyl group with carbon atoms of 1 to 4, lower alkoxy group with carbon atoms of 1 to 3, halogen atom, trifluoromethyl group, trifluoromethoxy group, phenyl group which is unsubstituted or may have substituents, phenoxy group which is unsubstituted or may have substituents or benzyloxy group which is unsubstituted or may have substituents], and by reducing (eighteenth process) the double bond of compounds represented by the general formula (17) 
[wherein B denotes a lower alkyl group with carbon atoms of 1 to 4, lower alkoxy group with carbon atoms of 1 to 3, halogen atom, trifluoromethyl group, trifluoromethoxy group, phenyl group which is unsubstituted or may have substituents, phenoxy group which is unsubstituted or may have substituents or benzyloxy group which is unsubstituted or may have substituents], or the general formula (18) 
[wherein B denotes a lower alkyl group with carbon atoms of 1 to 4, lower alkoxy group with carbon atoms of 1 to 3, halogen atom, trifluoromethyl group, trifluoromethoxy group, phenyl group which is unsubstituted or may have substituents, phenoxy group which is unsubstituted or may have substituents or benzyloxy group which is unsubstituted or may have substituents].
The fourteenth process can be performed in a solvent such as benzene, toluene, xylene or acetic acid, or without solvent. As the catalyst, secondary amine such as piperidine or pyrrolidine, or ammonium acetate can be used. The reaction can be performed at the reaction temperature of 0xc2x0 C. to 150xc2x0 C., preferably at refluxing temperature of the solvent.
The fifteenth process can be performed by reducing in a mixed solvent of alcohol such as ethanol or methanol with hydrochloric acid, using tin, tin chloride(II), tin amalgam or the like. The reaction can be performed at the reaction temperature of 0xc2x0 C. to 100xc2x0 C., preferably at room temperature to 50xc2x0 C.
The sixteenth process can be performed by leaving the carboxyl group as it is, or converting it to the reactive derivative.
In the case of the reaction using the reactive derivative, the reaction can be performed in a solvent such as dioxane or N,N-dimethylformamide in the presence or absence of, for example, alkali metal hydride such as sodium hydride, alkali metal hydroxide such as sodium hydroxide, alkali metal carbonate such as potassium carbonate, or organic base such as pyridine or triethylamine as a base.
In the case of conducting the reaction by leaving the carboxylic acid form as it is, the reaction can be performed in a solvent such as methylene chloride, chloroform, dioxane or N,N-dimethylformamide in the presence of condensing agent in the presence or absence of base, and in the presence or absence of additive.
As the condensing agent, for example, dicyclohexylcarbodiimide, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, diethyl cyanophosphate, diphenylphosphoric azide, carbonyldilmidazole or the like can be mentioned. As the base, for example, alkali metal hydroxide such as sodium hydroxide, alkali metal carbonate such as potassium carbonate, or organic base such as pyridine or triethylamine can be mentioned. As the additive, N-hydroxybenzotriazole, N-hydroxysuccinimide, 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine or the like can be mentioned. The reaction can be performed at the reaction temperature of xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably at 0xc2x0 C. to 50xc2x0 C.
The seventeenth process can be performed in a solvent such as ethyl acetate, tetrahydrofuran or N,N-dimethylformamide. The reaction can be performed at the reaction temperature of xe2x88x9220xc2x0 C. to 150xc2x0 C., preferably at 0xc2x0 C. to 100xc2x0 C.
The eighteenth process can be performed at a hydrogen pressure of 98.1 kPa to 491 kPa in a solvent such as ethanol, methanol, tetrahydrofuran, ethyl acetate or N,N-dimethylformamide in the presence of metallic catalyst such as palladium on carbon, platinum on carbon, platinum oxide or rhodium on alumina. The reaction can be performed at the reaction temperature of 0xc2x0 C. to 100xc2x0 C., preferably at room temperature to 80xc2x0 C.
Moreover, compounds, the bond mode of A portion being xe2x80x94CH2CH2COxe2x80x94 (1d) in the general formula (1), can be prepared, for example, through following processes (Scheme 5). 
Namely, compounds, the bond mode of A portion being xe2x80x94CH2CH2COxe2x80x94 (1d) in the general formula (1), can be prepared by reacting (nineteenth process) publicly known [Japanese Unexamined Patent Publication No. Hei 1-316363[ 5-formyl-2-methoxybenzoic acid (19) with N,O-dimethylhydroxylamine, then protecting (twentieth process) formyl group of N-methoxy-N-methyl-5-formyl-2-methoxybenzamide (20) with ethylene glycol to obtain N-methoxy-N-methyl-5-(1,3-dioxolane-2-yl)-2-methoxybenzamide (21). Then reacting (twenty-first process) (21) with magnesium methyl iodide, and reacting (twenty-second process) 3xe2x80x2-(1,3-dioxolane-2-yl)-2xe2x80x2-methoxyacetophenone (22) with diethyl carbonate in the presence of base, then reacting (twenty-third process) ethyl 3-[5-(1,3-dioxolane-2-yl)-2-methoxy- phenyl]-3-oxopropionate (23) with the compounds represented by the general formula (28) 
[wherein B denotes a lower alkyl group with carbon atoms of 1 to 4, lower alkoxy group with carbon atoms of 1 to 3, halogen atom, trifluoromethyl group, trifluoromethoxy group, phenyl group which is unsubstituted or may have substituents, phenoxy group which is unsubstituted or may have substituents or benzyloxy group which is unsubstituted or may have substituents], in the presence of base, followed by decarbonation reaction, to obtain compounds represented by a general formula (24) 
[wherein B denotes a lower alkyl group with carbon atoms of 1 to 4, lower alkoxy group with carbon atoms of 1 to 3, halogen atom, trifluoromethyl group, trifluoromethoxy group, phenyl group which is unsubstituted or may have substituents, phenoxy group which is unsubstituted or may have substituents or benzyloxy group which is unsubstituted or may have substituents]. Then reacting (twenty-fourth process) (24) with thiazolidine-2,4-dione in the presence of catalyst to obtain the compounds represented by the general formula (25) 
[wherein B denotes a lower alkyl group with carbon atoms of 1 to 4, lower alkoxy group with carbon atoms of 1 to 3, halogen atom, trifluoromethyl group, trifluoromethoxy group, phenyl group which is unsubstituted or may have substituents, phenoxy group which is unsubstituted or may have substituents or benzyloxy group which is unsubstituted or may have substituents], and by reducing (twenty-fifth process) the double bond of these compounds.
The nineteenth process can be performed by leaving carboxyl group as it is, or converting it to reactive derivative.
In the case of the reaction using the reactive derivative, the reaction can be performed in a solvent such as dioxane or N,N-dimethylformamide in the presence or absence of, for example, alkali metal hydride such as sodium hydride, alkali metal hydroxide such as sodium hydroxide, alkali metal carbonate such as potassium carbonate, or organic base such as pyridine or triethylamine as a base.
In the case of conducting the reaction by leaving the carboxylic acid as it is, the reaction can be performed in a solvent such as methylene chloride, chloroform, dioxane or N,N-dimethylformamide in the presence of condensing agent in the presence or absence of base, and in the presence or absence of additive.
As the condensing agent, for example, dicyclohexylcarbodiimide, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, diethyl cyanophosphate, diphenylphosphoric azide, carbonyldiimidazole or the like can be mentioned. As the base, for example, alkali metal hydroxide such as sodium hydroxide, alkali metal carbonate such as potassium carbonate, or organic base such as pyridine or triethylamine can be mentioned. As the additive, N-hydroxybenzotriazole, N-hydroxysuccinimide, 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine or the like can be mentioned. The reaction can be performed at the reaction temperature of xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably at 0xc2x0 C. to 50xc2x0 C.
The twentieth process can be performed in a solvent such as benzene, toluene or xylene in the presence of acid catalyst. As the acid catalyst, sulfuric acid, p-toluenesulfonic acid, camphorsulfonic acid, phosphorus oxychloride, oxalic acid or the like can be used. The reaction can be performed at the reaction temperature of 0xc2x0 C. to 150xc2x0 C., preferably at refluxing temperature of solvent.
The twenty-first process can be performed in a solvent such as ether, tetrahydrofuran or dioxane. The reaction can be performed at the reaction temperature of xe2x88x92100xc2x0 C. to room temperature, preferably at xe2x88x9280xc2x0 C. to 0xc2x0 C.
The twenty-second process can be performed in a solvent such as ether, tetrahydrofuran or dioxane in the presence of base. As the base, for example, alkali metal hydride such as sodium hydride, organometallic compound such as butyl lithium, metal amide such as lithium diisopropylamide, or metal alkoxide such as sodium methoxide or potassium t-butoxide can be used. The reaction can be performed at the reaction temperature of xe2x88x9220xc2x0 C. to 150xc2x0 C., preferably at 0xc2x0 C. to 50xc2x0 C.
For the twenty-third process, first, the alkylating reaction can be performed in a solvent such as ether, tetrahydrofuran or dioxane in the presence of base. As the base, for example, alkali metal hydride such as sodium hydride, organometallic compound such as butyl lithium, metal amide such as lithium diisopropylamide, or metal alkoxide such as sodium methoxide or potassium t-butoxide can be used. The reaction can be performed at the reaction temperature of xe2x88x9220xc2x0 C. to 150xc2x0 C., preferably at refluxing temperature of the solvent. Following decarbonation reaction can be performed under acidic condition. As the acid, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid or the like singly, or mixed solvents thereof can be used. The reaction can be performed at the reaction temperature of room temperature to 150xc2x0 C., preferably at refluxing temperature of the solvent.
The twenty-fourth process can be performed in a solvent such as benzene, toluene, xylene, ethanol or acetic acid, or without solvent. As the catalyst, secondary amine such as piperidine or pyrrolidine, or ammonium acetate can be used.
The reaction can be performed at the reaction temperature of 0xc2x0 C. to 150xc2x0 C., preferably at refluxing temperature of the solvent.
The twenty-fifth process can be performed at a hydrogen pressure of 98.1 kPa to 491 kPa in a solvent such as ethanol, methanol, tetrahydrofuran, ethyl acetate or N,N-dimethylformamide in the presence of metal catalyst such as palladium on carbon, platinum on carbon, platinum oxide or rhodium on alumina. The reaction can be performed at the reaction temperature of 0xc2x0 C. to 100xc2x0 C., preferably at room temperature to 80xc2x0 C.
As the administering form of the novel compounds of the invention, for example, oral administration with tablet, capsule, granule, powder, inhalant, syrup or the like, or parenteral administration with injection, suppository or the like can be mentioned.
Best embodiment to put the invention into practice